Targeting FLT3 for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia - PROJECT SUMMARY
Chimeric antigen receptor (CAR)-engineered T cell therapy has revolutionized treatment for certain B cell
malignancies, but similar successes for acute myeloid leukemia (AML) have not yet been shown, although interim
results of early phase clinical trials, including our own, are promising. We have constructed a CAR that targets
the type III receptor tyrosine kinase (RTK) called FLT3. Utilizing a patient-derived xenograft (PDX) model of
FLT3(+) human AML, we have shown that infusion of human FLT3-CAR T cells prolonged survival of AML-
bearing mice in the absence of other therapies. Further, FLT3-CAR T cells did not affect engraftment or survival
of hematopoietic stem cells (HSCs) in mice bearing AML. The effectiveness of FLT3-CAR T cell therapy in AML
will depend on (1) surface antigen density of FLT3 on AML blasts, including leukemic stem cells (LSC) relative
to normal HSCs, and (2) the ability of other immune effector cells to contribute to the eradication of AML in vivo.
To this end, we have discovered that treatment of AML blasts with an RTK inhibitor (TKI) upregulates the
expression of FLT3 on the AML blast and the LSC in vivo, relative to FLT3 expression on normal HSCs. To
advance a second cellular therapeutic intervention for AML, we have expressed the FLT3-CAR in human natural
killer (NK) cells to generate FLT3-CAR NK cells, which demonstrated potent anti-leukemic activity against
FLT3(+) AML. Collectively, these discoveries have led us to conclude that a program directed against FLT3(+)
AML has strong rationale, is innovative and could result in a significant decline in mortality for a subset of AML
patients. Therefore, the long-term objective of this proposal is to perform both preclinical and clinical studies
that will best define an optimal strategy to reduce mortality from AML with FLT3-CAR cellular therapy, either
alone or in combination with TKIs. Our central hypothesis is that targeting relapsed/refractory FLT3(+) AML
with FLT3-CAR T cells or FLT3-CAR NK cells in combination with TKIs will improve outcomes in AML. In this
proposal, we will assess the feasibility, safety and toxicity of performing a phase I study of human FLT3-CAR T
cell therapy directed against FLT3(+) AML (Aim 1), we will determine the mechanism by which TKIs upregulate
the surface density expression of FLT3 on LSCs and HSCs (Aim 2), and we will optimize a FLT3-CAR NK cell
platform and assess its functionality against AML alone or combined with TKI (Aim 3). To accomplish these
objectives, we have begun clinical manufacturing of FLT3-CAR T cells to treat eligible patients with refractory or
relapsed AML; we will utilize both human AML cell lines and patients' AML blasts in vitro as well as in vivo along
with our PDX model for our correlative and preclinical studies evaluating FLT3-CAR T and FLT3-CAR NK cells
in combination with TKI. Upon conclusion, we will understand how best to optimize cellular immune therapy to
cure AML. Further insight into this process, as will result from the implementation and completion of this proposal
is impactful as it will ultimately lead to a reduction in mortality for select patients suffering from AML.
